Conversion of fluorinated esters to ethers



United States Patent Ofllice i iifl l No Drawing. Filed Sept. 26, 1962, Ser. No. 226,434 Claims. (Cl. 260-397.4)

This invention relates to a new procedure-for the conversion of fluorinated esters to ethers. More particularly, this invention relates to conversion of aliphatic esters to aliphatic ethers by treatment of an aliphatic ester wherein the carbon atom bearing the acyloxy substituent is attached to a trifluoromethyl group, with alkali in an aliphatic alcohol. a

This application is 'a continuation-in-part of my copending applications Serial No. 127,776, filed June 20, 1961, now US. Pat. No. 3,076,824; Serial No. 129,987, filed August 8, 1961, now abandoned; and Serial No. 139,381, filed September 20, 1961, now US. Pat. No. 3,l07,256.- v

The steroid compounds which can be produced in pentylpropionic, cyclohexylacetic, fl-cyclohexylpropionic,-

trimethylacetic, diethylacetic, triethylacetic, acrylic, crotonic, methacrylic, phenylacetic, fi-phenylpropionic, naphthylacetic and similar acids.

The substituents represented by X and X in the foregoing reaction can be hydrogen atoms or any of a wide variety of organic radicals including aliphatic, aromatic and alicyclic radicals. X and X can represent aliphatic radicals, such as methyl, ethyl, propyl, butyl, amyl, hexyl, octyl, decyl, lauryl, cetyl, ceryl, carnaubyl, myricyl and similar alkyl radicals containing 1 to 30 carbon atoms. X'and X can also represent unsaturated aliphatic radicals, such as vinyl, allyl, crotyl, methallyl, propargyl and similar aliphatic radicals containing 2 to 30 carbon atoms containing one or more double or triple bonds. X and X can also stand for alicyclic radicals such as cyclopentyl, cyclohexyl, polyhydrophenanthryl and cyclopentanopolyhydrophenanthryl radicals which can contain further accordance with this-invention have useful physiological properties. They have adrenocortical activity and are useful in the relief of inflammation of rheumatoid arthritis and similar collagen and allergic conditions. They have particular utility in inducing thymolytic corticoid substituents, such as hydroxyl, alkoxyl, acyloxyL -acetal, and related substituents, as well as halogen atoms. X and X can also stand for aromatic, alicyclic andheterocyclic radicals, such as phenyl, tolyl, xylyl, naphthyl, phenanthryl, anthryl, acenaphthyl, chlorophenyl, bromophenyl, hydroxyphenyl, benzhydryl, benzopyranyl, benzyl, biphenylyl, bornyl, camphanyl, cinnamyl, cumyl, cyclohexenyl, cyclopentenyl, cyclopropyl, cymyl, fenchyl, furyl, menthyl, mesityl, phenetyl, 'pyranyLphytyl, pyrryl, pyrazolyl, pyrenyl, pyrimidyl, V quinolyl, styryl, thenyl,

veratryl and similar radicals- The organic radicals rep- The steroid compounds'produced herein are also, useful as intermediates in the synthesis of physio-logically active steroid compounds, and particularly adrenocorticoid compounds. The aliphatic compounds produced by the procedure of this invention are useful as refrigerants, insecticides and aerosol ingredients.

The procedure which comprises this invention can be illustrated by the following general equation:

wherein X and X represent hydrogen atoms or organic radicals and R and R represent aliphatic organic radicals. In this reaction, the procedure is conducted in an aliphatic alcohol represented by the formula ROH in the presence of an excess of alkali such as sodium, potassium or lithium hydroxide or sodium, potassium or lithium bicarbonate. The acyl radical, which is represented by RC0 is exchanged for an aliphatic radical represented.

by R, and the acyl radical forms an organic acid RCOOH, which is neutralized by the alkali present.

The foregoing reaction is of wide general applicability and is operative with the wide variety of esters of aliphatic acids, such as formic, acetic, propionic, butyric, isobutyric, valeric, caproic, 'heptoic, caprylic, nonylic, capric, undecylic, lauric, myristic, palmitic, stearic, oleic, linoleic, ricinoleic, chloroacetic, fluoroacetic, bromoacetic, trichloroacetic, trifluoroacetic, cyclopentylacetic, fl-cycloresented by X'and X' can be further substituted with hydroxy, 0x0, halogen, sulfhydryl, amino, carboxy, carbalkoxy, carbamido: and related substituents without afliecting the generality of the reaction. Y I

The reaction is conducted at relatively low temperature in an aliphatic alcohol in the presence of an excess of alkali. The reaction can be conducted at temperatures in the range of0 to 100 C. although temperatures 7 in the range of 15-50 C. are preferred. The reaction is complete within a few hours at ordinary temperatures (2025 C.) and is accelerated at higher temperatures. It the organic compound contains other reactive substituents, it may be desired to conduct the reaction at ordinary temperatures so that the other substituents will not become hydrolyzed or otherwise adversely aflfected by the alkali. When the reaction is carried out at ambient temperatures (2025 0.), there is no saponification of ordinary ester radicals under conditions where the desired acyloxy compound is converted to an aliphatic ether.

After the reaction is completed, the desired organic ether can be isolated by conventional procedures, such as acidification to neutralize the alkali present, followed by v stood by those skilled in the art that numerous modifications in starting materials, operating conditions, isolation procedures andthe like may be adopted without departing from the invention as herein disclosed.

' 220ml. of warm methanol.

fected solution of the reactants, I was kept at 25 C. for 15 hours, then acidified with 3 ml.

.3 EXAMPLEI' Conversiorz of 21-(2,2,Z-trifluoro-Lacetoxyezhyl)-all0- pz egnane-3p-ol-20-one acetate to 21-(2,2,2-triflu0ro-1- methoxyethyl)allopregnane-313-l-20-one acetate 0 O CH CHCFrr acetoxyethyl)allopregnane-3fi-ol-20-one acetate in'220 of warm methanol was added a solution of 2.2 gramsof' potassiumbicarbonate in'22 ml. of water. 1 The resulting mixture was warmed'and stirred for 15 minutes to efiect solution of the reactants and then left at room ternperai ture (20 C.) for 48 hours." The reaction mixture was 7 acidifiedwithS ml. of acetic acid and the solvent removed by evaporation on a steam bath. 7 Icewas added to the residue and the mixture was extracted with ether. The ether extract was washedwith 5% KHCO solution and with'water, dried, filtered and evaporated. The oily 21 7 (2,2,2 trifluorodrmethoxyethyl)allopregnane-3B-ol-20 one acetate was chromatographed onmagnesium silicate 61 4. mg. ofsolid product. Recrystallization from.heptane gave 302 mg. of21-(2,2,2-trifluoro-l-rnethoxyethyl) 'allopregnane-3B-ol-20-one acetate .of M.P. 135136, C.

' Further recrystallization from heptaneiraised the M. P to '13s 139c. 7 I

-. 'EXAMBLEII j Q conyers'ion of l6-(2,2,2-triflu0r0-1-acetoxyethyl) andros- A solution of 2.2 gams of KHCO in .22 ml. of water was added to a .solution of 2.2 grams of .16-(2,2,2-trifluoro-l-acetoxyethyl)androstane 3fi-ol-17-one. acetate in Stirring .and heating ef- The resultingsolution of acetic acid and evaporated under vacuum orra steam' bath. Ice was'added to the residue and the mixture was extracted with ether. The ether extract was washed with 5% KHCO solution. dried and evaporated. The residue of 16-(2,2;2-tfifluoroel methoxyethyl)androstane-irg-olf17-oneacetate was recrystallized from hexane; yield 308 mg; M.P.j.149-16Q 0; Further recrystallization from V ()JHOF:

('Florisil). and. the benzene-hexane (1:1) eluate yielded .7

ing mixture was kept at room-temperature for 5 hours,

V tracted with ether for 12 hours.

washed with water, dried and fractionally distilled. A

sorption spectrum of this compound had apealc at 5.74 7

microns. 7

' 7 EXAMPLE III- Con Version of j 16- (2,2,2-trifluoro-1 -acetoxyeihyl) i-andr os tmze-3 ,B-Ol-Z 7 -one acetate to 16-(2,2,2-triflu0r0-1 meth- I oxyethyl) andr0stane-3p-0l-l 7-0ne 0H; CH,

A solution of 0.5 gram of 1,6-(2,2,2trifluoro-lacetoxy- I ethyl)androstane-3/3-ol-17-one'acetate in 30 ml. of 5% methanolic KOH solution was allowed to'stand 1' hour at room temperature (20. (3.).

extract was washed with water, driedf-iand evaporated; The residue of 16-(2,2,2-trifluoro 1-methoxyethyl)androstane-3B-ol-17-oi1e was crystallized-fromjfi rnl. of heptane; yield 320 mg.,'M.P. 123-425". C. Further recrys- 'tallization raised the 'M.B.' to 125-127 C. .The LRfabsorption spectrum had maxirna at 3.07and 5.7-2 microns; Treatment of .16-'(2,2,2triflu0r9-lrmethoxyethyl) am; F drostane-3fi-ol-l7-one with an excessfof acetic'anlry clride; in anhydrouspyridine gave'16-(2,2,2-trifluoro l methoxye; ethyl)'-an'drostane-3 ,B-ol-17-oneacetate of MP. 160-162:

C. after recrystallization from hexane.

EXAMPLECIV in 500 ml. of warm ethanol was added a solutioncf. 10

grams of KHCO in 'm'l; ofSOfi C. water. The result-.

then neutralized with acetic acid. The reaction'mixture was diluted with 5.00 mllofwater and continuously ex- The ether extract was fraction distilling at .49-53 'c. was obtained and con sisted essentially of ethyl 2,2,2j-triflu oroethyl ether. 7 EXAMPLE v Conversion 0) '21 (2,2,2-trz'flaor o-l -acetoxyethyl allo:

pregnane-B-ol-ZO-one V acetate. to 21- (2,2,2-triflu0r0-1- methoxyethyl)allopregnane id-obz0-0112 i COCHgCHOF: H: (\q .OCOCH;

. 70113 J V .COCH CHCF CH: 7 K

The solution was then diluted with water and: extractedwith ether; The ether to an ether of the following formula wherein X and X represents members of the group consisting of hydrogen and organic radicals and R and R' represent aliphatic organic radicals, which comprises reacting said ester with an excess of an alcohol of the formula R'OH in the presence of an excess of alkali and isolating the organic ether thus formed.

2. A method of converting a steroid ester of the formula St-COCH -CHCF;

OCOR

to an ether of the formula St-COCHg-CH-C F;

wherein St is a polyhydrocyclopentanophenanthryl radical and R and R are aliphatic hydrocarbon radicals, which comprises reacting said ester with an alcohol of the formula R'OH in the presence of an excess of alkali and isolating the organic ether thus formed.

3. A method of converting a steroid ester of the formula St-CH-CFa OCOR to an ether of the formula snort-0F:

wherein St is a polyhydrocyclopentanophenanthryl radical and R and R are aliphatic hydrocarbon radicals, which comprises reacting said ester with an alcohol of the formula R'OH in the presence of an excess of alkali and isolating the organic ether thus formed.

4. The method of claim 2 wherein R and R are alkyl radicals containing 1 to 10 carbon atoms.

5. The method of claim 3 wherein R and R are alkyl radicals containing 1 to 10 carbon atoms.

6. Method of converting a 21 (2,2,2-trifluoro-1-hydroxy ethyl)allopregnane-3B-ol-20-one diester of an aliphatic carboxylic acid containing 1 to 18 carbon atoms to a 21-(2,2,2-trifluoro-l-alkoxyethyl)allopregnane-SB-ol- 20-one ester, wherein the alkyl radical contains 1 to 10 carbon atoms, which comprises reacting said diester with an alkanol containing 1 to 10 carbon atoms in the presence of alkali and isolating the ether thus formed.

7. Method of converting a 16-(2,2,2-trifluoro-1-hy droxyethyl)androstane-3fl-ol-17-one diester of an aliphatic carboxylic acid containing 1 to 18 carbon atoms to a 16- (2,2,2-trifluoro-l-alkoxyethyl)androstane-3fi-ol-17-one ester, wherein the alkyl radical contains 1 to 10 carbon atoms, which comprises reacting said diester with an alkanol containing 1 to 10 carbon atoms in the presence of alkali and isolating the ether thus formed.

8. The method of claim 6 wherein the aliphatic carboxylic acid is acetic acid and the alkanol is methanol.

9. The method of claim 7 wherein the aliphatic carboxylic acid is acetic acid and the alkanol is methanol.

10. In the method of converting an ester of the group consisting of substituted and unsubstituted fl,,6,,9-trifluoroethyl esters to an ether, the steps comprising reacting said ester with an excess of an alcohol in the presence of an excess of alkali and isolating the ether thus formed.

No references cited.

LEWIS GOTTS, Primary Examiner. 

1. A METHOD FOR CONVERTING AN ESTER OF THE FOLLOWING FORMULA
 6. METHOD OF CONVERTING A 21-(2,2,2-TRIFLUORO-1-HYDROXY ETHYL)ALLOPREGNANE-3B-OL-20-ONE DIESTER OF AN ALIPHATIC CARBOXYLIC ACID CONTAINING 1 TO 18 CARBON ATOMS TO A 21-(2,2,2-TRIFLUORO-1-ALKOXYETHYL)ALLOPREGNANE-3B-OL20-ONE ESTER, WHEREIN THE ALKYL RADICALCONTAINS 1 TO 10 CARBON ATOMS, WHICH COMPRISES REACTING SAID DIESTER WITH AN ALKANOL CONTAINING 1 TO 10 CARBON ATOMS IN THE PRESENCE OF ALKALI AND ISOLATING THE ETHER THUS FORMED. 